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      Therapeutics and Clinical Risk Management (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on reporting of clinical studies, outcomes and safety in all therapeutic areas and surgical intervention areas. Sign up for email alerts here.

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      Review of thalidomide in the treatment of newly diagnosed multiple myeloma

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          Abstract

          The role of thalidomide has been well established in the setting of relapsed or refractory multiple myeloma (MM). More recently, studies have been focused on upfront induction therapy. In newly diagnosed MM patients, thalidomide improved the response rates and the event-free survival induced by both high-dose and conventional chemotherapy regimens. The effect on survival needs to be further investigated. The efficacy of this drug is counterbalanced by a significant rate of both acute and long-term toxicities. Thus best timing of initiation, dosing schemes and duration of therapy is still unclear. Evidence is now emerging that clinical response can be achieved also at lower doses with minimal long term toxicity.

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          Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma.

          Chris G Richardson, T Hideshima, G. Müller … (2001)
          The antiangiogenic activity of thalidomide (Thal), coupled with an increase in bone marrow angiogenesis in multiple myeloma (MM), provided the rationale for the use of Thal in MM. Previously, the direct anti-MM activity of Thal and its analogues (immunomodulatory drugs, IMiDs) on MM cells was demonstrated, suggesting multiple mechanisms of action. In this study, the potential immunomodulatory effects of Thal/IMiDs in MM were examined. It was demonstrated that Thal/IMiDs do not induce T-cell proliferation alone but act as costimulators to trigger proliferation of anti-CD3-stimulated T cells from patients with MM, accompanied by an increase in interferon-gamma and IL-2 secretion. However, an increase in autologous T-cell killing of patient MM cells could not be demonstrated. A role for natural killer (NK)- and LAK-cell-mediated killing is suggested because IL-2-primed peripheral blood mononuclear cells (PBMCs) treated with Thal/IMiDs demonstrated significantly increased lysis of MM cell lines. Cold target inhibition assays suggested NK- rather than LAK-cell-mediated killing. Furthermore, this killing was not major histocompatibility complex-class restricted, and the depletion of CD56(+) cells blocked the drug-induced MM cell lysis. It was significant that increased killing of patient MM cells by autologous PBMCs treated with Thal/IMiDs was also observed. Although the in vivo relevance of NK-cell-mediated MM cell killing is unknown, phenotypic analysis performed in MM patients receiving Thal therapy demonstrated an increase in CD3(-)CD56(+) cells in patients responding to therapy. Thus in vitro and in vivo data support the hypothesis that Thal may mediate its anti-MM effect, at least in part, by modulating NK cell number and function.
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            Antitumor activity of thalidomide in refractory multiple myeloma.

            S. Singhal, J. Mehta, R Desikan … (1999)
            Patients with myeloma who relapse after high-dose chemotherapy have few therapeutic options. Since increased bone marrow vascularity imparts a poor prognosis in myeloma, we evaluated the efficacy of thalidomide, which has antiangiogenic properties, in patients with refractory disease. Eighty-four previously treated patients with refractory myeloma (76 with a relapse after high-dose chemotherapy) received oral thalidomide as a single agent for a median of 80 days (range, 2 to 465). The starting dose was 200 mg daily, and the dose was increased by 200 mg every two weeks until it reached 800 mg per day. Response was assessed on the basis of a reduction of the myeloma protein in serum or Bence Jones protein in urine that lasted for at least six weeks. The serum or urine levels of paraprotein were reduced by at least 90 percent in eight patients (two had a complete remission), at least 75 percent in six patients, at least 50 percent in seven patients, and at least 25 percent in six patients, for a total rate of response of 32 percent. Reductions in the paraprotein levels were apparent within two months in 78 percent of the patients with a response and were associated with decreased numbers of plasma cells in bone marrow and increased hemoglobin levels. The microvascular density of bone marrow did not change significantly in patients with a response. At least one third of the patients had mild or moderate constipation, weakness or fatigue, or somnolence. More severe adverse effects were infrequent (occurring in less than 10 percent of patients), and hematologic effects were rare. As of the most recent follow-up, 36 patients had died (30 with no response and 6 with a response). After 12 months of follow-up, Kaplan-Meier estimates of the mean (+/-SE) rates of event-free survival and overall survival for all patients were 22+/-5 percent and 58+/-5 percent, respectively. Thalidomide is active against advanced myeloma. It can induce marked and durable responses in some patients with multiple myeloma, including those who relapse after high-dose chemotherapy.
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              Thalidomide and hematopoietic-cell transplantation for multiple myeloma.

              Bart Barlogie, Frits van Griensven, Guido Tricot … (2006)
              High-dose therapy with melphalan can prolong survival among patients with multiple myeloma. We assessed whether the addition of thalidomide, which has activity against advanced and refractory myeloma, would further improve survival. Between October 1998 and February 2004, 668 patients with newly diagnosed multiple myeloma received two cycles of intensive melphalan-based chemotherapy, each supported by autologous hematopoietic stem-cell transplantation. A total of 323 were randomly assigned to receive thalidomide from the outset until disease progression or undue adverse effects, and 345 did not receive thalidomide. The primary end point was the five-year event-free survival rate. Secondary end points were complete response and overall survival. After a median follow-up of 42 months among survivors, the thalidomide and control groups had rates of complete response of 62 percent and 43 percent, respectively (P<0.001), and five-year event-free survival rates of 56 percent and 44 percent (P=0.01). The five-year rate of overall survival was approximately 65 percent in both groups (P=0.90). Median survival after relapse was 1.1 years in the thalidomide group and 2.7 years in the control group (P=0.001). Severe peripheral neuropathy and deep-vein thrombosis occurred more frequently in the thalidomide group than in the control group. When incorporated into high-dose therapy for myeloma, thalidomide increased the frequency of complete responses and extended event-free survival at the expense of added adverse effects without improving overall survival. (ClinicalTrials.gov number, NCT00083551.). Copyright 2006 Massachusetts Medical Society.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Ther Clin Risk Manag
                Journal ID (publisher-id): Therapeutics and Clinical Risk Management
                Title: Therapeutics and Clinical Risk Management
                Publisher: Dove Medical Press
                ISSN (Print): 1176-6336
                ISSN (Electronic): 1178-203X
                Publication date (Print): August 2007
                Publication date (Electronic): August 2007
                Volume: 3
                Issue: 4
                Pages: 543-552
                Affiliations
                Divisione di Ematologia dell’Universita’ di Torino Azienda Ospedaliera San Giovanni Battista, 10126 Torino, Italy
                Author notes
                Correspondence: Federica Cavallo, Divisione di Ematologia dell’Universita’ di Torino, Azienda Ospedaliera San Giovanni Battista, Via Genova 3, 10126 Torino, Italy Tel + 39 011 6336107 Fax + 39 011 6963737 Email federica1.cavallo@ 123456unito.it
                Article
                PMC ID: 2374936
                PubMed ID: 18472975
                SO-VID: 930a01c3-13c0-44aa-b580-873a7b178736
                Copyright statement: © 2007 Dove Medical Press Limited. All rights reserved
                History
                Categories
                Subject: Review

                ScienceOpen disciplines: Medicine
                Keywords: multiple myeloma,front-line therapy,thalidomide
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: multiple myeloma, front-line therapy, thalidomide

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